Most contemporary models of disease development consider the interaction between genotype and environment as static. The authors argue that because time is a key factor in genotype-environment interaction, this approach oversimplifies the pathology analysis and may lead to wrong conclusions. In reviewing the field, the authors suggest that the history of genotype-environment interactions plays an important role in the development of diseases and that this history may be analyzed using the phenotype as a proxy. Furthermore, a theoretical and experimental framework is proposed based on the assumption that phenotypes do not change from one to another randomly but are interconnected and follow certain phenotype trajectories. It then follows that analysis of such phenotype trajectories might be useful to predict the future phenotypes including the onset of disease. In addition, an analysis of phenotype trajectories can be subsequently used to choose better control subjects in comparative studies reducing noise and bias in studies investigating disease mechanisms.

Department of Pathological Physiology Faculty of Medicine Masaryk University Kamenice 5 Building A18 625 00 Brno Czech Republic Research Centre for Toxic Compounds in the Environment Faculty of Science Masaryk University Kamenice 5 Building A29 625 00 Brno Czech Republic

Research Centre for Toxic Compounds in the Environment Faculty of Science Masaryk University Kamenice 5 Building A29 625 00 Brno Czech Republic Institute of Biogeochemistry and Pollutant Dynamics ETH Zurich Universitätstrasse 16 CH 8092 Zürich Switzerland

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